Morese Pasquale A, Ahmad Ayaz, Martin Mathew P, Noble Richard A, Pintar Sara, Wang Lan Z, Xu Shangze, Lister Andrew, Ward Richard A, Bronowska Agnieszka K, Noble Martin E M, Stewart Hannah L, Waring Michael J
Cancer Research Horizons Newcastle Drug Discovery Unit, Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne, UK.
Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne, UK.
Commun Chem. 2025 Apr 9;8(1):111. doi: 10.1038/s42004-025-01501-6.
The discovery of targeted covalent inhibitors is of increasing importance in drug discovery. Finding efficient covalent binders requires modulation of warhead reactivity and optimisation of warhead geometry and non-covalent interactions. Uncoupling the contributions that these factors make to potency is difficult and best practice for a testing cascade that is pragmatic and informative is yet to be fully established. We studied the structure-reactivity-activity relationships of a series of analogues of the EGFR inhibitor poziotinib with point changes in two substructural regions as well as variations in warhead reactivity and geometry. This showed that a simple probe displacement assay that is appropriately tuned in respect of timing and reagent concentrations can reveal structural effects on all three factors: non-covalent affinity, warhead reactivity and geometry. These effects include the detection of potency differences between an enantiomeric pair that differ greatly in their activity and their capacity to form a covalent bond. This difference is rationalised by X-ray crystallography and computational studies and the effect translates quantitatively into cellular mechanistic and phenotypic effects.
在药物研发中，靶向共价抑制剂的发现变得越来越重要。寻找高效的共价结合剂需要调节弹头反应性，并优化弹头几何结构和非共价相互作用。区分这些因素对效力的贡献很困难，且尚未完全确立一个实用且信息丰富的测试级联的最佳实践方法。我们研究了一系列表皮生长因子受体（EGFR）抑制剂波齐替尼类似物的结构-反应性-活性关系，这些类似物在两个亚结构区域有位点变化，同时弹头反应性和几何结构也有所不同。结果表明，一个在时间和试剂浓度方面经过适当调整的简单探针置换试验，可以揭示对所有三个因素的结构影响：非共价亲和力、弹头反应性和几何结构。这些影响包括检测对映体对之间的效力差异，它们在活性和形成共价键的能力方面有很大差异。通过X射线晶体学和计算研究对这种差异进行了合理化解释，并且这种影响定量地转化为细胞机制和表型效应。
